Recent findings suggest that apoptosis or programmed cell death contributes to diabetic neuropathy, and, moreover, treatment with IGF-1 protects nerves by inhibiting glucose-induced apoptosis, apparently by signaling through the IGF-1 receptor, phosphatidylinositol 3-kinase (PI3K) and Akt. Akt in turn appears to phosphorylate and inhibit BAD, thereby interrupting an otherwise constitutive interaction of BAD with Bcl-xL, thereby freeing up Bcl-xL, which maintains mitochondrial integrity and prevents apoptosis. The present proposal will test this hypothesis in neural cells in three ways: (1) determine the role of IGF-I receptor-dependent signaling cascades in IGF-1 mediated neuroprotection; (2) examine the function of BAD phosphorylation and BAD/Bcl-xL association in IGF-mediated neuroprotection; and (3) characterize neuronal apoptosis and clinical endpoints of diabetic neuropathy in streptozotocin-diabetic rats treated with IGF-1. The ultimate goal is to understand the pathogenesis of diabetic neuropathy, and develop new treatment strategies for this problem.